Pyranocoumarin derivatives

ABSTRACT

The present invention relates to compounds of the following formula (I) or pharmaceutically acceptable salts thereof. The present invention also relates to use for a cognitive-enhancing agent of compounds of the following formula (I) or pharmaceutically acceptable salts thereof and to a process for preparing the same. Further, the present invention relates to use for a congnitive-enhancing agent of decursin of the following formula (II) or pharmaceutically acceptable salts thereof. In addition, the present invention relates to extracts of Angelica gigantis Radix comprising decursin of the following formula (II), having cognitive-enhancing effects.

TECHNICAL FIELD

The present invention relates to pyranocoumarin derivatives having thefollowing general formula:

-   -   , wherein R₁ and R₂ each represent hydrogen or C₁₋₄alkoxy,    -   or pharmaceutically acceptable salts thereof.

BACKGROUND ART

Senile dementia has recently been recognized as a degenerative centralnerve system disorder. The number of patients suffering from the diseasehas been increased to become a serious social problem, and so theprevention, amelioration, and treatment of the disease are nowconsidered very important.

Alzheimer's disease, vascular diseases, Parkinson's disease,hypothyroidism, and alcoholic dementia are known as disorders which maycause dementia, but more than 50% of the patients suffering from seniledementia are found to suffer from Alzheimer's disease. The central nervesystem of the patients suffering from Alzheimer's disease is generallyimpaired, and particularly, cholinergic neuron is most severelyimpaired. Thus, the studies to develop therapeutic agents to improvecholinergic neuronal functions have been vigorously conducted.

A method to improve the functions of impaired cholinergic neuron is toadminister cholinergic receptor agonist or acetylcholinesterase (AChE)inhibitor to inhibit degradation of acetylcholine (ACh), a cholinergicneurotransmitter, and thereby to maintain the concentration of synapticACh.

However, cholinergic receptor agonist has a disadvantage to be readilydegraded in vivo, and thus, AChE inhibitor is generally used. That is,AChE inhibitor ameliorates the conditions of senile dementia bypreventing the degradation of AChE by inhibiting the activity of AChE,an enzyme to degrade ACh, and maintaining the concentration of synapticAch, and thereby sustaining a series of cholinergic receptor-mediatedreactions.

This is supported by the fact that most of the drugs that have beendeveloped as therapeutic agents for Alzheimer's disease and currently onclinical use or trial are AChE inhibitors. AChE inhibitors that havebeen approved by the United States Food and Drug Administration and usedas therapeutic agents of dementia are exemplified by tacrine (THA,Cognex®), donepezil (Aricept®), rivastigmaine (Exelon®), andgalanthamine (Reminyl®) that is most recently approved. However, theseAChE inhibitors are known to have such problems as hepatotoxicity, shorthalf-life, low bioavailability, etc. Thus, more studies have beenperformed to develop a novel AChE inhibitor.

The present inventors have tested various natural products for AChEinhibitory activity to identify the activity with using in vivoexperimental models by finding a substance with AChE inhibitory activityfrom the natural products that have been used as traditional Korean folkmedicines for a long time. As a result, the present inventors found outthat a methanolic extract of Angelicae gigantis Radix has significantAChE inhibitory activity and cognition-enhancing activity.

Angelicae gigantis Radix is an herbal medicine used as a sedative, ananalgesic, or a tonic agent, and particularly an essential drug usedafter childbirth for anemia and women's diseases, etc. by sedative andmenstruation-promoting actions. In Korea, the dried root of Angelicagigas Nakai has been used as Angelicae gigantis Radix.

Further, the present inventors isolated and purified active ingredientsshowing AChE inhibitory and cognition-enhancing activities fromAngelicae gigantis Radix, and synthesized many compounds by using theactive ingredients as starting materials and tested them for theircognition-enhancing activity. As a result, they found out pyranocoumarinderivatives of the general formula (I) have cognition-enhancingactivity. Therefore, the present inventors completed the presentinvention.

DISCLOSURE OF THE INVENTION

The present invention provides pyranocoumarin derivatives of thefollowing general formula:

-   -   , wherein R₁ and R₂ each represent hydrogen or C₁₋₄alkoxy,    -   or pharmaceutically acceptable salts thereof.

The present invention also provides an agent for enhancing cognition,comprising the compounds of the above general formula (I) orpharmaceutically acceptable salts thereof.

The present invention further provides a process for preparing thecompounds of the above general formula (I).

The present invention still further provides an agent for enhancingcognition, comprising decursin of the following formula:

-   -   or a pharmaceutically acceptable salt thereof as an active        ingredient.

The present invention still further provides an extract of Angelicaegigantis Radix, comprising decursin of the above formula (II).

Hereinafter, the present invention will be explained in detail.

One aspect of the present invention provides novel compounds of thegeneral formula:

-   -   , wherein R₁ and R₂ each represent hydrogen or C₁₋₄alkoxy, and        preferably, R₁ is OCH₃, and R₂ is hydrogen.

Another aspect of the present invention provides a process for preparingthe compounds of the general formula (I) by conventional esterificationreaction of decursinol (a) with phenyl propanoids (b), as depicted inthe following reaction scheme:

The starting material, decursinol (a), may be prepared by directextraction of Angelicae gigantis Radix, or by alkaline hydrolysis ofdecursin of the above formula (II), one ingredient of Angelicae gigantisRadix.

The present inventors first confirmed that decursin of formula (II), oneingredient of Angelicae gigantis Radix, has cognition-enhancingactivity, synthesized many compounds using the ingredients of Angelicaegigantis Radix as starting materials, and screened the compounds fortheir cognition-enhancing activity. As a result, the present inventorsfound that the compounds of the general formula (I) have superiorcognition-enhancing activity.

A third aspect of the present invention provides an agent for enhancingcognition, comprising the compounds of the general formula (I) as anactive ingredient.

The compounds of the general formula (I) according to the presentinvention can be formulated according to methods known in pharmaceuticalfield. The compounds alone or in admixture with pharmaceuticallyacceptable carriers, excipients, etc. are manufactured into conventionalpharmaceutically acceptable dosage forms, for example, injectableformulations, solutions, syrups, tablets, capsules and the like. Thecompounds of the general formula (I) according to the present inventionmay be converted into pharmaceutically acceptable inorganic or organicsalts using conventional pharmaceutical methods. They may beadministered by oral or parenteral route.

The dose of the compounds of the general formula (I) according to thepresent invention may be appropriately selected depending uponabsorption rate and excretion rate of the active ingredient, patient'sage, body weight, sexuality and condition, and severity of disease totreat, and generally, their daily dose is in the range of 0.01 to 500mg/kg, and preferably, 0.1 to 200 mg/kg to an adult. The compounds offormula (I) of the present invention may be administered several timeswith a regular interval, if necessary.

A fourth aspect of the present invention provides an agent for enhancingcognition, comprising decursin of the above formula (II) as an activeingredient.

Decursin of the present invention may be extracted from Angelicaegigantis Radix, or synthesized using conventional methods. One exampleof the extraction method of Angelicae gigantis Radix in the presentinvention is as follows.

The root of Angelica gigas Nakai is extracted with C₁₋₄alcohol, forexample, methanol, ethanol, propanol, etc., and the obtained extract issuspended in water, and then, partitioned with dichloromethane (CH₂Cl₂)to obtain water fraction and dichloromethane fraction. Thedichloromethane fraction is further purified by column chromatography onsilica gel (for example, using n-hexane:CHCl₃:MeOH as an eluent), andrecrystallized to obtain decursin.

The above extract of Angelicae gigantis Radix and decursin according tothe present invention have excellent cognition-enhancing activity.

Decursin and extract of Angelicae gigantis Radix according to thepresent invention may be formulated according to methods known inpharmaceutical field, and decursin of the present invention may beconverted into pharmaceutically acceptable inorganic or organic saltsthereof according to conventional pharmaceutical methods.

Doses of decursin and Angelica gigantis Radix extract of the presentinvention are generally in the range of 0.01 to 500 mg/kg, andpreferably, 0.1 to 200 mg/kg a day to an adult. The extract of Angelicaegigantis Radix according to the present invention may be administered at0.01 to 500 mg once to three times a day, and decursin of the presentinvention may be administered at 0.1 to 200 mg once to three times aday.

As used herein, the term “Angelicae gigantis Radix” means the root ofAngelica gigas, the term “C₁₋₄alcohol” means methanol, ethanol,propanol, isopropanol or butanol, for example, and the term “C₁₋₄alkoxy”means methoxy, ethoxy, propoxy, isopropoxy or butoxy, for example.

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention will be more specifically illustrated by thefollowing examples. However, the following examples should not beconstrued to limit the scope of the present invention.

EXAMPLE 1 Extraction and Fractionation of Angelicae gigantis Radix

The dried root of Angelica gigas (5 kg) was finely powdered, andextracted with MeOH in an ultrasonic apparatus to obtain a methanolicextract (350 g). The extract was suspended in water, and partitionedwith CH₂Cl₂ to obtain CH₂Cl₂ fraction (220 g).

EXAMPLE 2 Isolation and Structural Identification of Decursin from theExtract of Angelicae gigantis Radix

The CH₂Cl₂ fraction of Angelica gigas obtained in Example 1 wassubjected to column chromatography on silica gel (n-hexane:CHCl₃:MeOH)to obtain 7 fractions (AG-C-01 to 07). A part of AG-C-03 of thosefractions was recrystallized with EtOH to isolate 678 mg of Compound 1.The compound emitted purple fluorescence at UV of long wavelength (365nm), and developed purple color with anisaldehyde-H₂SO₄.

Compound 1:

Colorless prism

C₁₉H₂₀O₅

EIMS (m/z) (rel. int.): 328[M]⁺ (0.7), 228 (21.4), 213 (100.0), 83(24.7), 55 (20.1)

¹H NMR (300 MHz, CDCl₃): δ 1.31 (3H, s, CH ³ 2′), 1.33 (3H, s, CH ³ 2),1.83 (3H, d, J=1.2 Hz, CH₃-4″), 2.09 (3H, d, J=1.2 Hz, CH ³ -3″), 2.85(1H, dd, J=4.9, 17.3 Hz, H-4′), 3.18 (1H, dd, J=4.9, 17.3 Hz, H-4′),5.04 (1H, t, J=4.9 Hz, H-3′), 5.61 (1H, m, H-2″), 6.19 (1H, d, J=9.5 Hz,H-3), 6.74 (1H, s, H-5), 7.11 (1H, s, H-8), 7.56 (1H, d, J=9.5 Hz, H-4)ppm

¹³C NMR (75 MHz, CDCl₃): δ 20.3 (3″-CH₃), 23.1 (2′-CH₃), 25.0 (2′-CH₃),27.5 (C-4″), 27.9 (C-2′), 69.1 (C4′), 76.6 (C-3′), 104.7 (C-8′), 112.8(C-10′), 113.2 (C-3), 115.5 (C-2″), 115.9 (C-6), 128.6 (C-5), 143.1(C-4), 154.1 (C-9), 156.4 (C-7), 158.5 (C-3″), 161.3 (C-2), 165.7 (C-1″)

Chemical formula:

Compound 1 was identified as decursin by comparing the abovephysicochemical properties and spectroscopic results with those in theliterature (Ahn, K. S. et al. (1996) Decursin: A cytotoxic agent andprotein kinase C activators from the root of Angelica gigas, Planta Med.62: 7-9).

EXAMPLE 3 Preparation of Pyranocoumarin Derivatives of the GeneralFormula (I)

(1) Alkaline Hydrolysis of Decursin

Decursin of 1 g obtained from Example 2 was dissolved in 40 ml of 5%ethanolic KOH, and a reaction was performed at 60° C. for 1 hour. Thereaction mixture was cooled and thereto was added water to terminate thereaction. Then, the reaction mixture was partitioned with ethyl acetate.The fraction was concentrated and recrystallized with chloroform toobtain Compound 2 (680 mg).

Compound 2 emitted blue fluorescence at UV of long wavelength (365 nm),and developed purple color with anisaldehyde-H₂SO₄.

Compound 2:

C₁₄H₁₄O₄

Colorless needles

EIMS (m/z) (rel. int.): 246 [M]⁺

¹H NMR (300 MHz, CDCl₃): δ 1.34 (3H, s, gem-CH₃), 1.37 (3H, s, gem-CH₃),2.81 (1H, m, H-4′), 3.09 (1H, m, H-4′), 3.85 (1H, t, J=5.0 Hz, H-3′),6.20 (1H, d, J=9.5 Hz, H-3), 6.76 (1H, s, H-5), 7.16 (1H, s, H-8), 7.56(1H, d, J=9.5 Hz, H-4) ppm

¹³C NMR (75 MHz, CDCl₃): δ 22.0 (gem-CH₃), 25.0 (gem-CH₃), 30.6 (C-2′),69.1 (C4′), 78.1 (C-3′), 104.7 (C-8), 112.9 (C-10), 113.3 (C-3), 116.4(C-6), 128.9 (C-5), 143.1 (C4), 154.1 (C-9), 156.4 (C-7), 161.2 (C-2)ppm

Compound 2 was identified as decursinol by comparing the abovephysicochemical properties and spectroscopic results with those in theliteratures (Konoshima et al. (1968) Coumarins from the root of Angelicagigas Nakai. Chem. Pharm. Bull. 16: 1139-1140; and Seong et al. (1988)Studies on the constituents of the roots of Angelica flaccida Kommarov.Kor. J. Pharmacogn. 19: 233-238).

(2) Synthesis and Isolation of Compound 3

As depicted in the following reaction scheme, Compound 2(a) obtainedfrom the above (1) of 246 mg (1 mmol), p-methoxycinnamic acid (c) of 356mg (2 mmol), and 4-(dimethylamino)-pyridine (DMAP) of 122 mg (1 mmol)were dissolved in 10 ml of anhydrous dichloromethane, and a reaction wasperformed under nitrogen at room temperature for 5 minutes. Then,1,3-dicyclohexyl carbodiimide (DCC) of 300 mg (1.5 mmol) was addedthereto, and the reaction was further performed for 2 hours. Thereaction mixture was cooled and filtered through Celite 545, and then,the filtrate was subjected to column chromatography on silica gel(hexene:ethyl acetate=2:1) to isolate Compound 3 (250 mg).

(3) Structural Identification of Compound 3

C₂₄H₂₂O₆

EIMS (m/z): 406 [M]⁺, 246 [M-160]⁺

¹H NMR (300 MHz, CD₃OD): δ 1.28 (3H, s, gem-CH₃), 1.30 (3H, s, gem-CH₃),2.84 (1H, dd, J=17.5, 4.6 Hz, H_(α)-4′), 3.18 (1H, dd, J=18.4, 4.6 Hz,H_(β)-4′), 3.69 (3H, s, OCH₃), 3.99 (1H, q, J=7.1 Hz, H-3′), 6.10 (1H,d, J=9.5 Hz, H-3), 6.10 (1H, d, J=15.84 Hz, H-7″), 6.64 (1H, s, H-5),6.80 (2H, d, J=8.9 Hz, H-3″, 5″), 7.24 (1H, s, H-8), 7.39 (2H, d, J=8.9Hz, H-2″, 6″), 7.50 (1H, d, J=15.84 Hz, H-8″), 7.69 (1H, d, J=9.5 Hz,H-4) ppm

¹³C NMR (75 MHz, CDCl₃): δ 22.0 (gem-CH₃), 23.8 (gem-CH₃), 27.3 (C-2′),54.4 (OCH₃), 70.0 (C4′), 76.7 (C-3′), 103.6 (C-8), 112.1 (C-3), 112.9(C-10), 114.0 (C-3″, 5″), 114.1 (C-7″), 116.3 (C-6), 126.7 (C-1″), 129.1(C-5), 129.7 (C4″, 6″), 144.1 (C-4), 145.4 (C-8″), 153.9 (C-9), 156.6(C-7, 4″), 161.8 (C-2), 166.6 (C-9″) ppm

Chemical formula:

From the above physicochemical properties and spectroscopic results,Compound 3 was identified as8,8-dimethyl-7-[3-(4-methoxyphenyl)-2E-propenoxy]-2H,6H-benzoyl[1,2-b:5,4-b′]dipyran-2-one(IUPAC name; 3-(4-methoxyphenyl)-acrylicacid-2,2-dimethyl-8-oxo-3,4-dihydro-2H,8H-pyrano[3,2-g]cromen-3-ylester).

Experiment 1: Activity Test of Angelicae gigantis Radix Extract

(1) Measurement of Cholinesterase Inhibitory Activity

AChE inhibitory activity of the methanolic extract and CH₂Cl₂ fractionof Angelica gigas of the above Example 1 was measured by the method ofEllman et al. (Ellman, et al. (1961) A new and rapid colorimetricdetermination of acetylcholinesterase activity, Biochem. Pharmacol. 7:88-95).

To a test tube containing a chromogen (5,5-dithiobis-2-nitrobenzoicacid) and a sample was added AChE homogenated with phosphate bufferedsaline (Electric eel Type V-S, Sigma), and a reaction was performed at37° C. for 5 minutes, and thereto was added a substrate for the enzyme,acetylcholine iodide, and a reaction was further performed at 37° C. for3 minutes. Neostigmine bromide was added thereto to terminate thereaction, and then, the absorbance was measured at 412 nm to obtain AChEinhibition (%). The above procedure was repeated with no AChE as ablank, or with no sample as a control. The results are shown in thefollowing Table 1. TABLE 1 (concentration: 100 μg/ml) FractionInhibition (%) Methanolic fraction 42.1 CH₂Cl₂ fraction 49.3 Waterfraction 19.7

As shown in the above Table 1, the methanolic extract and CH₂Cl₂fraction of Angelica gigas according to the present invention had betterAChE inhibitory activity than the water fraction.

(2) Passive Avoidance Test

Male ICR mice weighing 25 to 30 g that had been bred with sufficientwater and feed in the Experimental Animal Breeding Center of SeoulNational University were supplied and adapted to the laboratoryenvironment for 1 week to be used in this experiment.

An avoidance box (40×20×20 cm) equipped with 3 mm stainless steel rodspaced 0.5 cm apart at the bottom was divided into a light compartmentand a dark compartment, and when mice placed in the light compartmententered the dark compartment, an electrical shock (0.1 mA/10 g bodyweight) was delivered through the stainless steel rods. The aboveprocedure was repeated after 24 hours, and the time for which the micestayed at the light compartment was measured and used as an index ofmemorizing the training of the previous day. Passive avoidance test wasperformed according to the method of Christensen et al. (Cholinergic‘Blockade’ as a model of the cognitive deficits in Alzheimer's disease,Brain 115: 1681-1699, 1992). Specifically, scopolamine was dissolved inphysiological saline to 1.5 mg/kg solution, and the solution wassubcutaneously injected to mice 30 minutes before the training to induceamnesia. The Angelica gigas extract was intraperitoneally injected tothe mice 1 hour before the scopolamine administration, and observed forits effect on the scopolamine-induced amnesia. The results are shown inthe following Table 2. TABLE 2 Effect of methanolic extract and CH₂Cl₂fraction of Angelicae gigantis Radix on passive avoidance in mice withscopolamine-induced amnesia Treatment (mg/kg) Step-through latency(seconds) Saline 158.8 ± 27.6  Scopolamine 1.5 29.7 ± 3.1  Scopolamine1.5 + AG T 100  64.2 + 7.6*** + AG C 10  48.3 ± 9.3*** + AG C 50  87.9 ±9.9***AG T: total methanolic extract of A. gigas,AG C: CH₂Cl₂ fraction of A. gigasThe data is expressed as Mean ± S.D., and the significance is ***p <0.001.

As shown in the above Table 2, the methanolic extract andCH₂Cl₂-fraction of Angelica gigas according to the present inventionincreased step-through latency in passive avoidance test to haveexcellent cognition-enhancing activity.

Experiment 2: Activity Test of Decursin and Compound 3 of Example 3

(1) Measurement of Cholinesterase Inhibitory Activity

AChE inhibitory activity of decursin of the above Example 2 and Compound3 of the above Example 3 was measured according to the method inExperiment 1.

To a test tube containing a chromogen (5,5-dithiobis-2-nitrobenzoicacid) and a sample was added AChE homogenated with phosphate bufferedsaline (Electric eel Type V-S, Sigma), and a reaction was performed at37° C. for 5 minutes, and thereto was added a substrate for the enzyme,acetylcholine iodide, and a reaction was further performed at 37° C. for3 minutes. The above procedure was repeated with no AChE as a blank orwith no sample as a control. Neostigmine bromide was added thereto toterminate the reaction, and then, the absorbance was measured at 412 nmto obtain IC₅₀ of AChE inhibition. The results are shown in thefollowing Table 3. TABLE 3 IC₅₀ Decursin (Compound 1) 4.8 × 10⁻⁴ MCompound 3 5.1 × 10⁻⁵ M Decursinol (Comparative Example) 2.8 × 10⁻⁵ M

As shown in the above Table 3, decursin and Compound 3 according to thepresent invention had better AChE inhibitory activity than decursinol(Comparative Example).

(2) Passive Avoidance Test

Passive avoidance test was performed according to the method of theabove Experiment 1(2) to measure effects of pyranocoumarin derivativesof the present invention. Velnacrine (AChE inhibitor) was used as apositive control.

Results for decursin are shown in the following Table 4, and those forCompound 3 are in the following Table 5. TABLE 4 Effects of decursin(Compound 1) and decursinol (Comparative example 1) on passive avoidancein mice with scopolamine- induced amnesia Treatment (mg/kg) Step-throughlatency (seconds) Saline 172.0 ± 16.0  Scopolamine 1.5 29.7 ± 2.8 Scopolamine 1.5 + decursinol 1 52.1 ± 8.8* decursinol 5  54.4 ± 10.6*decursinol 10 43.2 ± 7.7* Scopolamine 1.5 + decursin 0.5 32.1 ± 13.4decursin 1  108.6 ± 15.0** decursin 5  96.5 ± 18.2* Scopolamine 1.5 +velnacrine 1  73.4 ± 6.4**The data is expressed as Mean ± S.D., and the significance is *p < 0.05,**p < 0.01.

TABLE 5 Effects of Compound 3 on passive avoidance in mice withscopolamine-induced amnesia Treatment (mg/kg) Step-through latency(seconds) Saline 179.7 ± 0.6  Scopolamine 1.5 28.4 ± 10.1 Scopolamine1.5 + Compound 3 1 42.0 ± 17.9 Compound 3 2   86.0 ± 18.2*** Compound 35  171.2 ± 18.7***The data is expressed as Mean ± S.D., and the significance is ***p <0.001.

As shown in the above Table 4, decursin showed excellentcognition-enhancing activity by remarkably increasing step-throughlatency in in vivo passive avoidance test, whereas decursinol(Comparative example) did not show such activity.

As shown in the above Table 5, Compound 3 of Example 3 according to thepresent invention also showed excellent cognition-enhancing activity byremarkably increasing step-through latency in in vivo passive avoidancetest.

Hereinafter, formulation examples of the present invention will bedescribed. Formulation 1 Decursin 10 mg Distilled water for injectionq.s. pH adjusting agent q.s.

Decursin was dissolved in distilled water for injection, and a pHadjusting agent was added thereto to the pH of about 7.6. Then, theresulting solution was adjusted to the final volume of 2 ml, and then,filled into an ampoule with the volume of 2 ml and sterilized to preparean injectable solution. Formulation 2 Compound 3 of Example 3 2 mgDistilled water for injection q.s. pH adjusting agent q.s.

Compound 3 was dissolved in distilled water for injection, and a pHadjusting agent was added thereto to the pH of about 7.2. Then, theresulting solution was adjusted to the final volume of 2 ml, and then,filled into an ampoule with the volume of 2 ml and sterilized to preparean injectable solution. Formulation 3 Methanolic extract of Angelicagigas of Example 1  10 mg Lactic acid 100 mg Starch 100 mg Magnesiumstearate q.s.

The above ingredients were mixed and the mixture was compressed intotablets according to a conventional method to manufacture tablets.Formulation 4 Compound 3 of Example 3  10 mg Lactic acid 100 mg Starch 50 mg Magnesium stearate q.s.

The above ingredients were mixed and the mixture was compressed intotablets according a conventional method to manufacture tablets.Formulation 5 Decursin  5 mg Lactic acid 50 mg Starch 50 mg Talc  2 mgMagnesium stearate q.s.

The above ingredients were mixed and the mixture was filled into gelatincapsules according a conventional method to manufacture capsules.Formulation 6 Compound 3 of Example 3 5 mg Lactic acid 100 mg Starch 93mg Talc 2 mg Magnesium stearate q.s.

The above ingredients were mixed and the mixture was filled into gelatincapsules according a conventional method to manufacture capsules.Formulation 7 Compound 3 of Example 3 50 mg Sucrose 20 mg Isomerizedsugar 20 mg Lemon flavor q.s. Distilled water ad 100 ml

The above ingredients were mixed according to a conventional method tomanufacture solutions, and the solution was filled into a brown bottleof 100 ml and sterilized to prepare a solution. Formulation 8 Decursin100 mg Sucrose 20 mg Isomerized sugar 20 mg Lemon flavor q.s. Distilledwater ad 100 ml

The above ingredients were mixed according to a conventional method tomanufacture solutions, and the solution was filled into a brown bottleof 100 ml and sterilized to prepare a solution.

INDUSTRIAL APPLICABILITY

As can be seen from the above, the methanolic extract and CH₂Cl₂ factionof Angelicae gigantis Radix, decursin (II), and pyranocoumarinderivatives of the above general formula (I) have excellentcognition-enhancing activity, and can be effectively used as ananti-dementia agent.

1. A pyranocoumarin derivative of the following general formula:

, wherein R₁ and R₂ each represent hydrogen or C₁₋₄alkoxy, or apharmaceutically acceptable salt thereof.
 2. An agent for enhancingcognition, comprising the compound of the general formula (I) as definedin claim 1 or a pharmaceutically acceptable salt thereof as an activeingredient.
 3. A process for preparing the compound of the generalformula (I) as defined in claim 1, comprising the step of esterifyingdecursinol of the following formula:

with a phenyl propanoid of the following general formula:


4. An agent for enhancing cognition, comprising decursin of thefollowing formula:

or a pharmaceutically acceptable salt thereof as an active ingredient.5. An extract of Angelicae gigantis Radix, comprising decursin of claim4.